# s100a4 Signaling in Fibrotic Diabetic Tendon Healing

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $338,800

## Abstract

Effective surgical repair of tendon injuries is limited due to a propensity for scar tissue mediated healing rather
than regeneration of native tendon structure. This fibrotic scar tissue results in impaired tendon function due to
extracellular matrix (ECM) disorganization and inferior mechanical properties, relative to healthy tendon. Type
II Diabetes Mellitus (T2DM) dramatically exacerbates this healing paradigm resulting in a more profound loss
of tendon function, and increased incidence of re-rupture. Our understanding of the mechanisms that govern
increased fibrotic healing in diabetic tendon remains limited, and this gap in knowledge has resulted in a
paucity of therapeutic targets to improve clinical outcomes. Our previous studies have utilized a murine model
of diet-induced obesity and T2DM that results in increased scar-formation and inferior mechanical properties
during tendon healing, however, the mechanisms driving these impairments in healing are unknown. Our
preliminary data identify extracellular S100a4 (S100 calcium binding protein 4A) signaling as a key driver of
fibrotic tendon healing in non-diabetic animals. S100a4-haploinsufficiency decreases scarring and accelerates
improvements in mechanical properties, relative to WT, while S100a4-cell depletion also decreases scar tissue
formation, but decreases mechanical properties, suggesting that S100a4-producing cells are required for
mechanically sufficient tendon healing. Given that S100a4 and RAGE expression are dramatically increased in
diabetic tendon repairs we propose that fibrotic healing occurs to a greater degree in diabetic tendons than
non-diabetic due to elevated S100a4-RAGE signaling. Thus, in the present study we will use a murine model
diet induced obesity and T2DM in conjunction with acute tendon injury and repair to test the central hypothesis
that inhibition of the increased and sustained activation of pro-fibrotic S100a4-RAGE activity in diabetic
tendons will promote mechanically superior, regenerative tendon healing. We will test this hypothesis through
the following specific aims: Aim 1: Identify the S100a4-producing cell population during tendon healing and the
specific effects of S100a4 conditional deletion on scar tissue formation and acquisition of mechanical strength
after injury in diabetic tendons. Aim 2: Define the effects of global and macrophage-specific deletion of RAGE
on scar-mediated diabetic tendon healing as a mechanism of reduced S100a4 signaling. Aim 3: Assess the
efficacy of small molecule inhibition of S100a4 and RAGE to improve diabetic tendon healing.

## Key facts

- **NIH application ID:** 9879627
- **Project number:** 5R01AR073169-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Alayna Loiselle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,800
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879627

## Citation

> US National Institutes of Health, RePORTER application 9879627, s100a4 Signaling in Fibrotic Diabetic Tendon Healing (5R01AR073169-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9879627. Licensed CC0.

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